Disease mechanism

Hypophosphatasia (HPP) is caused by inactivating mutations in the ALPL gene, which is located on the short arm of chromosome 1 (1p36.1-34). This gene has the designation TNSALP (tissue-nonspecific alkaline phosphatase) or ALPL (bone/liver/kidney ALP) and more than 300 different mutations have been described: 2015 TNSALP Gene Mutations Database

The TNSALP gene codes for the tissue-specific isoenzyme of alkaline phosphatase (ALP). The consequences of low ALP activity and accumulation of ALP substrate can be life-threatening or lead to serious disease complications.

As with many genetic diseases, the underlying pathological processes linked to HPP are permanent throughout life – even though sometimes symptoms do not appear until later in life.

Low ALP activity results in extracellular accumulation of PLP, the active form of vitamin B6. Without dephosphorylation via ALP, vitamin B6 cannot pass into the central nervous system, which can result in a PLP deficiency in the central nervous system and associated vitamin B6-related seizures. The neurological symptoms can also be caused and worsened by craniosynostosis and accompanying raised intracranial pressure.

PPi is a natural inhibitor of bone mineralisation. When ALP activity is too low, PPi accumulates, disrupting bone mineralisation. This severely impairs bone formation and stability and calcium deposits to bone. This results in skeletal deformities and other pathological consequences, and can also produce other systemic consequences:

Atypical, repeated and/or slow-healing fractures

Nephrocalcinosis and kidney disorders

Craniosynostosis and accompanying raised intracranial pressure

Severe hypomineralisation of the ribs that can lead to pulmonary hypoplasia and respiratory failure

Chondrocalcinosis and rheumatological problems, with chronic pain and inflammation